| Autor: |
Fey SK; CRUK Beatson Institute, Glasgow, United Kingdom., Najumudeen AK; Institute for Molecular Medicine Finland, Helsinki, Finland, Finland., Watt DM; CRUK Scotland Institute, Glasgow, United Kingdom., Millett LM; Cancer Research UK Beatson Institute, United Kingdom., Ford CA; Cancer Research UK Beatson Institute, Glasgow, Scotland, United Kingdom., Gilroy K; Beatson Institute for Cancer Research, Glasgow, United Kingdom., Simpson RJ; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., McLay K; University of Glasgow, Glasgow, East Dunbartonshire, United Kingdom., Upstill-Goddard R; University of Glasgow, Glasgow, United Kingdom., Chang D; University of Glasgow, Glasgow, United Kingdom., Clark W; Beatson Institute for Cancer Research, Glasgow, United Kingdom., Nixon C; CRUK Scotland Institute, Glasgow, United Kingdom., Birch JL; University of Glasgow, Glasgow, East Dunbartonshire, United Kingdom., Barry ST; AstraZeneca (United Kingdom), Cambridge, United Kingdom., Morton JP; CRUK Beatson Institute, Glasgow, United Kingdom., Campbell AD; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Sansom OJ; CRUK Beatson Institute, Glasgow, United Kingdom. |
| Abstrakt: |
Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. While the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrated that wild-type KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of wild-type KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer. |
